POS0434 A NOVEL TARGET FOR TREATMENT OF INFLAMMATORY JOINT DISEASES
Authors: S. Lindquist, H. Persson, A. Roos, L. Lundberg, O. Hernell
Journal: Annals of the Rheumatic Diseases (2022)

Background A significant number of patients with inflammatory joint disorders do not respond or experience a waning effect to currently available pharmaceuticals, which emphasizes a high medical need for new efficacious drugs operating through novel targets and modes of action. One unexplored novel target is Bile Salt-Stimulated Lipase (BSSL). We have shown that patients with rheumatoid arthritis (RA), psoriasis arthritis (PsA), and juvenile idiopathic arthritis (JIA) have increased BSSL plasma levels compared to healthy controls, and that these levels correlate with disease activity scores. Moreover, conventional BSSL knockout mice are protected from developing disease in several recognized in vivo arthritis models and antibodies targeting BSSL prevent or mitigate arthritis in rodent models 1 . We have further shown that BSSL is secreted from activated granulocytes, binds to monocytes and stimulates their migration in vitro. With that knowledge, we developed a humanized anti-BSSL antibody (SOL-116) that blocks BSSL from binding to monocytes and we are now evaluating SOL-116 as candidate drug for treatment of chronic inflammatory joint diseases, including RA, PsA and JIA in man. Objectives The aim of the present study was to characterize SOL-116’s biological activity in vitro and verify the therapeutic efficacy in the pristane induced arthritis (PIA) rat model. Methods The affinity of SOL-116 to human, mouse and rat BSSL was measured by surface plasmon resonance biosensor technology. The epitope on human BSSL was mapped by hydrogen deuterium exchange mass spectrometry (HDX-MS) and confirmed by crystallization of SOL-116 Fab-fragments with human BSSL. For efficacy evaluation, arthritis was induced in DA rats by administration of pristane. SOL-116 at three different doses (10, 30 and 90 mg/kg) or vehicle control were administered subcutaneously on day 5, 10 and 15 after disease induction. Disease activity was evaluated daily from day 7 in a blinded fashion using a macroscopic scoring system of the four limbs. To gain knowledge about the mechanism of action, the effect of SOL-116 on BSSL induced cell migration was evaluated using a transwell migration assay. Results SOL-116 binds to human, mouse, and rat BSSL, although a single amino acid deviation in the BSSL epitope results in approximately 80-fold lower affinity to rodent compared to human BSSL protein. In the efficacy validation study, treatment with highest dose SOL-116 (90 mg/kg) significantly mitigated disease severity in the PIA rats (Figure 1A). The relatively high doses of SOL-116 were chosen to compensate the low affinity for rat BSSL. A decrease in disease severity was also seen with SOL-116 at 30 mg/kg and 10 mg/kg, indicating a dose response, albeit not statistically significant. The plasma concentration of SOL-116 at day 19 correlated significantly to the arthritis score (Figure 1B). Mechanistic studies show that BSSL stimulates migration of CD14+ monocytes, and that SOL-116 prevents this effect in a dose dependent manner. Figure 1. Arthritis development and SOL-116 exposure in rats following pristane injection. ( A ) Animals treated with SOL-116 (90 mg/kg) show significantly lower disease severity compared to vehicle treated animals. Results are presented as mean ± SEM. ( B ) Plasma concentration of SOL-116 at day 19 in animals treated with 90 mg/kg correlates to disease severity. Conclusion The present study verifies that BSSL plays an important role in inflammation and that SOL-116 is a promising biologic drug candidate for novel treatment of chronic inflammatory joint diseases. References [1]Lindquist S, Andersson EL, Lundberg L, Hernell O. Bile salt-stimulated lipase plays an unexpected role in arthritis development in rodents. PLoS One. 2012;7(10):e47006. Acknowledgements The authors are grateful to Mrs. Eva-Lotta Andersson for excellent technical assistance. Disclosure of Interests Susanne Lindquist Shareholder of: Lipum AB, Umeå, Sweden, Grant/research support from: Lipum AB, Employee of: Lipum AB, Helena Persson: None declared, Annette Roos: None declared, Lennart Lundberg Shareholder of: Lipum AB, Consultant of: Lipum AB, Grant/research support from: Lipum AB, Employee of: Lipum AB, Olle Hernell Shareholder of: Lipum AB, Consultant of: Lipum AB, Grant/research support from: Lipum AB, Employee of: Lipum AB.